Microfungi can be classified as yeasts and filamentous fungi. Microfungi are capable of causing a variety of diseases in the oral cavity and the surrounding area. Mycotic diseases may arise as part of a systemic microfungal infection or may be derived from an independent infection which establishes in the oral cavity. Oral mycoses and their treatment are an important problem in oral medicine and have been reviewed in Kostiala, I. et al., Acta Odontol. Scand. 37:87-101 (1987), incorporated herein by reference.
Many factors can predispose a patient to an opportunistic microfungal infection in the oral cavity. For example, general debilitation or poor oral hygiene are predisposing factors. Patients who are being treated with antibiotics, steroids, or cytostatic therapy, patients with AIDS, diabetes mellitus or other immunodeficiency or hormonal diseases, patients with malignant tumors or a hematogenous disorder are all at a high risk for opportunistic fungal infections. In addition, certain age groups such as infants, the elderly, and pregnant women are at a higher risk of oral fungal infections.
Mechanical trauma from an ill-fitted prosthesis is also a major cause of oral microfungal infections. One report estimated that Candida was involved in 60% of the cases of "denture sore mouth" (denture stomatitis) in the elderly (Budtz-Jorgensen, E. et al., Community Dent. Oral Epidemiol. 3:115 (1975)). Denture stomatitis appears to be a manifestation of a cell-mediated hypersensitivity reaction to the microfungal infection.
It is important to treat oral mycotic infections as soon as possible. Untreated infections may become the foci for systemic dissemination of the yeast or fungus, with potentially fatal results in severely compromised patients. For example, disseminated candidosis is the second most common opportunistic infection in patients with AIDS (Odds, F. C., CRC Crit. Rev. Microbiol. 15:1-5 (1987)).
The most important species of microfungi which have been implicated as being involved in superficial or deep mycotic infections in the oral cavity include Candida albicans. C. tropicalis, C. stellatoidea, C. pseudotropicalis. C. parapsilosis, C. quilliermondii, C. krusei, and C. vixwanathii, all of which have been implicated in candidosis; Torulopsis glabrata which is the cause of torulpsidosis; Geotrichum candidum, which is the cause of geotrichosis; Rhizopus, Mucor, Absidia, and Basidiobolus which are the cause of aspergillosis, Cryptococcus neoformans, the cause of cryptococcosis; Blastomyces dermatitidis, the cause of blastomycosis; Paracoccidioides brasiliensis, the cause of paracoccidioidomycosis; Sporothrix schenkii, the cause of sporotrichosis; Rhinosporidium seeberi, the cause of rhinosporidoisis; Histoplasma capsulatum, the cause of histoplasmosis; Histoplasma duboisii, the cause of African histoplasmosis, Coccidiodes immities, the cause of coccidioidomycosis, Trichophyton mentagrophytes, T. rubrum, T. tonsurans and T. violaceum, the causes of dermatophytosis; and, Rhinocladiella or Phialophora, and Cladosporium, the causes of chromomycosis.
The Candida species is the most virulent of the fungi which infect the oral mucosa. Pathogenic Candida species are aerobic yeasts that can also grow anaerobically. C. albicans, the Candida species most often responsible for infections of the oral cavity, grows in two morphological forms: either as a budding yeast, or as a continuously extending hyphae which extends into tissue. In the oral cavity, Candida may cause a variety of disorders based on localization of the infection such as pulpitis, gingivitis, tonsillitis, cheilitis, glossitis, stomatitis, pharyngitis, laryngitis and sinusitis.
Oral candidosis has been classified into different categories based on the clinical and histopathological manifestations of the infection (Lehner, T., in Clinical Aspects of immunology, P.G.H. Gell, et al., eds., 3rd edition, Blackwell Scientific Publications, Oxford, 1975, pp.1387-1427).
Acute Pseudomembranous candidosis, or thrush, primarily affects children or patients with debilitating diseases (Crawson, R. A., Dent. Res. 15:361-364 (1965). C. albicans is a major causative agent of thrush in the newborn.
The clinical signs which usually appear first are creamy-white, soft, nonkeratotic plaques which appear on the mucosa of the tongue, cheeks, gum and pharynx. The plaque is easily rubbed off, leaving an inflamed mucosa underneath. There may be no subjective symptoms until the plaque spreads to the pharynx, larynx or esophagus, where it may cause dysphaghia, soreness and dryness of the tongue, a sore throat or symptoms of cheilitis.
Acute atrophic candidosis is a form of thrush which is consistently painful, and which is thought to arise as a consequence of the shedding of the fungal plaque from its site of attachment to the tissue. It can be found on the dorsum linguae, or associated with angular cheilitis and inflammation of cheeks and lips.
Chronic atrophic candidosis, or denture stomatitis is the term given to Candida-based infections of the denture-bearing tissues. Torulopsis glabrata is also associated with some forms of denture stomatitis.
Chronic mucocutaneous candidosis refers to four different types of candidosis which are resistant to treatment and which are associated with patients with a heterogeneous pattern of immunodeficiencies. These types of candidosis include chronic oral hyperplastic candidosis, which predominately affects adult males between the ages of 30 and 70; chronic localized mucocutaneous candidosis, which starts in childhood as an intractable oral Candida infection and later manifects itself as lesions in the nails, and skin of the fingers and toes; chronic localized mucocutaneous candidosis with granuloma which primarily affects young girls, starting in the mouth but later manifesting itself as horny masses of the face, scalp and upper respiratory tract; and, chronic localized mucocutaneous chadidosis with endocrine disorder, also found most frequently in young girls, and associated with lesions of the tongue, cheek, oral commissures and nails.
The establishment of a mycotic infection in the oral cavity presents a serious health problem to the host which must be treated and contained. Treatment of mycotic diseases is directed to controlling this flora.
The most widely used approach to date to control microfungi in the oral cavity has been mechanical cleaning methods such as brushing the teeth. Although this method has proved to be fairly successful in treating individuals, there is still a high recurrence rate. There is also the problem of motivating people to good oral hygiene habits that they will maintain throughout their lives.
Systemic administration of antimycotics per os or intravenously has been used to control mycotic infections, however, discontinuation of therapy often results in the return of the pathogens to the oral cavity. Long-term systemic antimycotic therapy in doses high enough to control oral infections are undesirable for treatment of oral infections because the potential dangers and side-effects associated with this form of treatment include the development of resistant strains and superimposed infections, gastrointestinal irritation, liver damage and neurological symptoms, among others.
Antifungal agents have also been used in the form of mouth rinses, dentifrices, solutions and gels but have not proven to be completely successful in preventing fungal infections. A main problem with these techniques is that the antifungal drug does not remain in the oral cavity long enough at efficacious levels.
Another serious problem with antifungal drugs is that they are by necessity directed towards controlling an infection by a eukaryotic fungal cell in a eukaryotic host. As a result, drugs effective against the fungus also tend to be toxic to the host. Thus it is important to develop methods which permit the localized, sustained application of the toxic drug in a manner and dosage which is efficacious but which minimizes toxicity the host. Especially, it is important to develop methods which use low doses of the drug.
A topical, sustained-release form of an antifungal agent, could help maintain a locally efficacious level of the antifungal drug in the oral cavity and prevent these side effects. Such a dosage form might also prevent undesirable systemic side effects by releasing the drug at a lower therapeutic level over a long period of time in a localized manner. Ridgway, F. et al.. U.S. Pat. No. 4,725,440, describes a soft, antifungal drug-containing pastille or troche which is free of rough edges and will not adhere to oral mucosa, but which only releases anti-fungal medications within the 15-90 minutes while it dissolves in the mouth.
Cyr et al., U.S. Pat. No. 3,312,594 describes long lasting troches or pastilles for the treatment of oral lesions which include an anhydrous adhesive based on pectin, gelatin and carboxymethylcellulose and which, when wetted, adhere to the oral mucous membranes. However, the Cyr formulation was not well-tolerated by patients (Ridgway, F. et al., U.S. Pat. No. 4,725,440).
Sustained release has been reported to be achieved by embedding chlorhexidine in an ethyl cellulose polymer to form a varnish (Friedman, M., et al., J. Perio. Res. 17:323-328 (1982); Friedman, M., et al., IADR Prog. and Abstr. 59:No. 905 (1980)). This dosage form was used in the local treatment of periodontal disease (Soskolne, W. A., et al., J. Perio. Res. 18:330-336 (1983)) and in the treatment of plaque prevention in patients wearing orthodontic appliances (Friedman, M., et al., J. Dent. Res. 64:1319-1321 (1985)). A drawback to this plaque preventative system was that although plaque accumulation was decreased by the application of a varnish composed of chlorhexidine embedded in an ethyl cellulose polymer, the effectiveness of the system in decreasing plaque accumulation was present only for a period of four days subsequent to administration of the varnish. Friedman et al., (J. Dent. Res., supra), concluded that "clearly the conditions in the oral cavity and the formulation used do not, at present, facilitate such prolonged prevention of plaque accumulation." These authors also suggested that by altering the varnish components and method of preparation it might be possible in clinical use to sustain the necessary level of antibacterial agent release for longer periods. No suggestion was made in this publication as to how this could be accomplished.
Mastic has been used previously for dental purposes. U.S. Pat. No. 4,668,188 (Wolfenson, G. B.) discloses the use of a curable mastic in the production of an oral impression tray for making impressions of teeth and jaw structures. Mastics have been used in the production of dental molds (VonWeissenfluh, H. U.S. Pat. No. 4,500,288), as an adhesive to secure dental articulators (U.S. Pat. Nos. 4,548,581 and 4,382,787, Hoffman, R. E.) and as a tooth decay preventative (Wahmi U.S. Pat. No. 4,374,824). U.S. Pat. Nos. 4,532,126 and 4,428,927 (Ebert, W. R., et al.) disclose chewable, filled, one-piece soft elastic gelatin capsules, made chewable by a masticatory substance, such as a synthetic mastic.
U.S. Pat. No. 4,459,277 (Kosti, C. M.) relates to novel plaque compositions for use in evaluating oral hygiene practices. In brief, the patent discloses a water-insoluble, water-immiscible dye emulsified in fine droplets or rupturable capsules. The patent discloses the use of mastic resin as well as alginates, and other gums as an insoluble media for dye dispersion. In particular, sodium carboxymethylcellulose is disclosed. Also disclosed is the possibility of incorporating antibacterial agents such as stannous fluoride into the compositions. Significantly, the Kosti patent is concerned with diagnostic rather than therapeutic applications. The patent fails to suggest compositions exhibiting long-term preventive activity.
The background art fails to identify any compositions of matter comprising an effective antifungal agent together with a long-term sustained-release carrier, in combination with an adhesive polymer such as a mastic and a plasticizer such as polyethylene glycol, for use as an antifungal preventative varnish in the oral cavity by humans and other animals, under conditions in which the antimycotic agents have no deleterious medical side effects, and do not cause staining of the teeth. Another highly desirable characteristic not found in the art of record is that the antifungal agent should be released from the composition, not only in a sustained fashion, but over a sufficiently long period of time so as not to require excessive application of the composition.